An integrated metabonomic investigation of acetaminophen toxicity in the mouse using NMR spectroscopy

被引:196
作者
Coen, M
Lenz, EM
Nicholson, JK
Wilson, ID
Pognan, F
Lindon, JC
机构
[1] Univ London Imperial Coll Sci Technol & Med, Fac Med, Biol Chem Biomed Sci Div, London SW7 2AZ, England
[2] AstraZeneca, Drug Metab & Pharmacokinet, Macclesfield SK10 4TG, Cheshire, England
[3] AstraZeneca, Safety Assessment, Wilmington, DE 19850 USA
关键词
D O I
10.1021/tx0256127
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
An integrated metabonomics study using high-resolution H-1 NMR spectroscopy has been applied to investigate the biochemical composition of intact liver tissue (using magic angle spinning), liver tissue extracts, and blood plasma samples obtained from control and acetaminophen-treated mice. Principal components analysis was used to visualize similarities and differences in biochemical profiles. The time- and dose-dependent biochemical effects of acetaminophen were related to the drug toxicity, as determined using histopathology. Metabolic effects in intact liver tissue and lipid soluble liver tissue extracts from animals treated with the high dose level of acetaminophen included an increase in lipid triglycerides and monounsaturated fatty acids together with a decrease in polyunsaturated fatty acids, indicating mitochondrial malfunction with concomitant compensatory increase of peroxisomal activity. In addition, a depletion of phospholipids was observed in treated liver tissue, which suggested an inhibition of enzymes involved in phospholipid synthesis. There was also a depletion in the levels of liver glucose and glycogen. In addition, the aqueous soluble liver tissue extracts from high dose animals also revealed an increase in lactate, alanine, and other amino acids, together with a decrease in glucose. Plasma spectra showed increases in glucose, acetate, pyruvate, and lactate. These observations all provide evidence for an increased rate of glycolysis. These findings could indicate a mitochondrial inability to use pyruvate in the citric acid cycle and also reveal the impairment of fatty acid beta-oxidation in liver mitochondria of such treated mice.
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页码:295 / 303
页数:9
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